The delivery of any therapeutic compound to an individual or a patient in need thereof may be impeded by any one or several factors such as limited ability of the compound to reach a target cell or tissue, or by restricted entry or trafficking of the compound within cells. Various delivery vectors have been developed to encapsulate and deliver many classes of drugs and have proven a promising strategy to effectively treat cancers, diabetes, cardiovascular diseases, and many other disorders. For anionic drugs, such as proteins and nucleic acids, safe and effective delivery to the desired disease locations or intracellular sites remains a major challenge. This is, at least in part, due to the intrinsic properties of these drugs. Most proteins have high molecular weight (MW), surface charges, and/or vulnerable tertiary structures (Gu et al, Chem. Soc. Rev. 2011, 40:3638). Nucleic acids have the similar issues. Many nucleic acids are stable for only limited times in cells or plasma. Nucleic acid drugs should usually be delivered into the corresponding intracellular target site, i.e. the nucleus or cytosol. Specific and robust delivery vehicles are needed to facilitate loading, delivery, and controlled release of anionic drugs, especially for proteins and nucleic acids.
Numerous platforms have been developed as carriers of anionic proteins, and nucleic acids. Microspheres (Langer et al, Nature 1976, 263: 797; Kang et al, J. Controlled Rel. 2012, 160: 440) and hydrogels (Vermonden et al, Chem. Rev. 2012, 112: 2853; Peppas et al, K, Expert Opinion on Biological Therapy 2004, 4: 881) have been utilized to solve the sustained protein and nucleic acid release issue. These systems have limited applications for intracellular protein and nucleic acid delivery due to their large size. Platforms such as liposomes (Swaminathan et al, Expert Opinion on Drug Delivery 2012, 9:1489. Yan et al, Polymer Reviews 2007, 47:329.), conjugates (Duncan et al, Journal of Drug Targeting 2006, 14:337; Duncan, Nat Rev Drug Discov 2003, 2:347), nanotubes (Brahmachari et al, Angewandte Chemie International Edition 2011, 50:11243), and polymeric nanoparticles (Kamaly et al, PNAS 2013, 110:6506; Rana et al, Current Opinion in Chemical Biology 2010, 14:828) are being extensively investigated for effective intracellular delivery. These platforms often suffer from low loading of the negatively charged drug and release profiles characterized by a large initial burst release.
The anionic proteins, anionic protein analogues and nucleic acids are negatively charged and have complicated, sensitive, and fragile 3-D structure with nm scale sizes. There remains a need for materials and methods to load and encapsulate proteins and nucleic acids with high efficiency and high loading, and release them in a sustained manner while maintaining their bioactivity.
It is therefore an object of the invention to provide improved materials, compositions, and formulations for drug delivery, especially of negatively charged drugs such as proteins and nucleic acids.
It is an additional object of the invention to provide compositions with high loading efficiency of negatively charged drugs such as proteins and nucleic acids.
It is also an object of the invention to provide compositions with sustained release of active agents, including sustained release of negatively charged drugs such as proteins and nucleic acids.
It is a further object of the invention to provide methods of making improved materials, compositions, and formulations for drug delivery, especially of negatively charged drugs such as proteins and nucleic acids.
It is additionally an object of the invention to provide methods of using the materials, compositions, and formulations to delivery negatively charged drugs to a patient in need thereof.